Somatic stem cell populations reside in adult tissues and participate in the maintenance and regeneration of adult tissues. The signaling networks that govern the somatic stem cell populations are ill defined. We have previously defined the forkhead/winged helix transcription factor, Foxk1, as the first molecular marker for the muscle stem cell population that resides in adult skeletal muscle. Using a gene disruption strategy, mice lacking Foxk1 have impaired muscle regeneration, decreased numbers of muscle stem cells that have perturbed cell cycle kinetics and an induction of the cyclin dependent kinase inhibitor, p21. We provide new preliminary data supporting a novel pathway whereby Foxk1 contributes to a repression complex that represses p21 resulting in the activation and proliferation of the muscle stem cell population. These preliminary data provide a platform for the studies, outlined in this revised grant application. The overall hypothesis of this proposal is that lineage specific transcriptional regulators interact and modulate the myogenic stem cell population to promote skeletal muscle regeneration. To address this hypothesis, we will pursue the following three specific aims: Specific Aim #1: To define the transcriptional regulation of the cyclin dependent kinase inhibitor, p21CIP in the muscle stem cell population. Specific Aim #2: To define the transcriptional role of Foxk1 as a critical regulator of the muscle stem cell population. Specific Aim #3: To define the functional role of Foxk1 overexpression in adult skeletal muscle. These studies will enhance our understanding of the transcriptional regulation of the myogenic stem cell population and the mechanisms, in part, that govern muscle regeneration following an injury or disease. Furthermore, the results of these studies will serve as a platform for therapeutic strategies directed towards the treatment of acquired myopathic diseases. PUBLIC HEALTH RELEVANCE: Congenital and acquired myopathies are common and deadly. The capacity of adult tissues to regenerate in response to disease or injury is due to resident stem cell populations. The regulatory mechanisms that govern muscle stem cells are unknown. This proposal will decipher the molecular pathways that govern muscle stem cells and may ultimately lead to novel therapies directed towards an enhanced regenerative response in patients with myopathic diseases.